Honors & Awards
Research Fellow, The Alfred P. Sloan Foundation (2002)
Young Investigator Award, The Arnold and mabel Beckman Foundation (2002)
Speaker's Fund for Biomedical Research Award, New York Academy of Sciences (2002)
Career Scientist Award, Monique Weill-Caulier Trust (2002)
McKnight Scholar Award, The McKnight Endowment Fund for Neurosciences (2002)
Brain Disorders Award, The McKnight Endowment Fund for Neurosciences (2008)
Ph.D., Cornell University, Genetics and Development (1995)
B.S., Fudan University, Genetics (1987)
Current Research and Scholarly Interests
Our laboratory is interested in understanding how the diverse neuronal cell types are generated and maintained in the nervous system. We are taking a combined molecular, cellular, genetic, and genomic approach in the model organisms Drosophila and mouse. To study how neuronal diversity is generated, we focus on investigating the mechanisms of asymmetric division of neural stem cell that balances the self-renewal and differentiation potentials of neural stem cells. Of particular interest to us is the mechanism by which aberrant regulation of neural stem cell asymmetric division leads to brain tumor-like phenotypes. To study how neurons are properly maintained after they are integrated into neural networks, we are creating neurodegenerative phenotypes in Drosophila similar to that observed in Alzheimers and Parkinsons diseases in humans. We are employing the power of fly genetics to identify genetic modifiers that can suppress or enhance these disease phenotypes. Given the unanticipated high level conservation of signaling pathways, regulatory mechanisms, and physiological processes between flies and mammals, our research promises to provide insights into fundamental mechanisms that control the generation and maintenance of neuronal diversity in humans.
Independent Studies (9)
- Directed Reading in Cancer Biology
CBIO 299 (Aut, Sum)
- Directed Reading in Neurosciences
NEPR 299 (Aut, Sum)
- Directed Reading in Pathology
PATH 299 (Aut, Win, Spr, Sum)
- Early Clinical Experience in Pathology
PATH 280 (Aut, Win, Spr, Sum)
- Graduate Research
CBIO 399 (Aut, Sum)
- Graduate Research
NEPR 399 (Aut, Sum)
- Graduate Research
PATH 399 (Aut, Win, Spr, Sum)
- Medical Scholars Research
PATH 370 (Aut, Win, Spr, Sum)
- Undergraduate Research
PATH 199 (Aut, Win, Spr, Sum)
- Directed Reading in Cancer Biology
PINK1 and Parkin Control Localized Translation of Respiratory Chain Component mRNAs on Mitochondria Outer Membrane.
2015; 21 (1): 95-108
Mitochondria play essential roles in many aspects of biology, and their dysfunction has been linked to diverse diseases. Central to mitochondrial function is oxidative phosphorylation (OXPHOS), accomplished by respiratory chain complexes (RCCs) encoded by nuclear and mitochondrial genomes. How RCC biogenesis is regulated in metazoans is poorly understood. Here we show that Parkinson's disease (PD)-associated genes PINK1 and Parkin direct localized translation of certain nuclear-encoded RCC (nRCC) mRNAs. Translationally repressed nRCC mRNAs are localized in a PINK1/Tom20-dependent manner to mitochondrial outer membrane, where they are derepressed and activated by PINK1/Parkin through displacement of translation repressors, including Pumilio and Glorund/hnRNP-F, a Parkin substrate, and enhanced binding of activators such as eIF4G. Inhibiting the translation repressors rescued nRCC mRNA translation and neuromuscular-degeneration phenotypes of PINK1 mutant, whereas inhibiting eIF4G had opposite effects. Our results reveal previously unknown functions of PINK1/Parkin in RNA metabolism and suggest new approaches to mitochondrial restoration and disease intervention.
View details for DOI 10.1016/j.cmet.2014.12.007
View details for PubMedID 25565208
Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway.
Genes & development
2013; 27 (24): 2642-2647
The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.
View details for DOI 10.1101/gad.225169.113
View details for PubMedID 24352421
View details for PubMedCentralID PMC3877754
Tricornered/NDR kinase signaling mediates PINK1-directed mitochondrial quality control and tissue maintenance
GENES & DEVELOPMENT
2013; 27 (2): 157-162
Eukaryotes employ elaborate mitochondrial quality control (MQC) to maintain the function of the power-generating organelle. Parkinson's disease-associated PINK1 and Parkin actively participate in MQC. However, the signaling events involved are largely unknown. Here we show that mechanistic target of rapamycin 2 (mTORC2) and Tricornered (Trc) kinases act downstream from PINK1 to regulate MQC. Trc is phosphorylated in mTORC2-dependent and mTORC2-independent manners and is specifically localized to mitochondria in response to PINK1, which regulates mTORC2 through mitochondrial complex-I activity. Genetically, mTORC2 and Trc act upstream of Parkin. Thus, multiplex kinase signaling is acting between PINK1 and Parkin to regulate MQC, a process highly conserved in mammals.
View details for DOI 10.1101/gad.203406.112
View details for Web of Science ID 000314044800005
View details for PubMedID 23348839
Parkinson's Disease-Associated Kinase PINK1 Regulates Miro Protein Level and Axonal Transport of Mitochondria
2012; 8 (3)
Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. In Drosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkin mutations. Moreover, the different effects of loss of PINK1 function on Miro protein level in Drosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species.
View details for DOI 10.1371/journal.pgen.1002537
View details for Web of Science ID 000302254800014
View details for PubMedID 22396657
View details for PubMedCentralID PMC3291531
Regulation of cell growth by Notch signaling and its differential requirement in normal vs. tumor-forming stem cells in Drosophila
GENES & DEVELOPMENT
2011; 25 (24): 2644-2658
Cancer stem cells (CSCs) are postulated to be a small subset of tumor cells with tumor-initiating ability that shares features with normal tissue-specific stem cells. The origin of CSCs and the mechanisms underlying their genesis are poorly understood, and it is uncertain whether it is possible to obliterate CSCs without inadvertently damaging normal stem cells. Here we show that a functional reduction of eukaryotic translation initiation factor 4E (eIF4E) in Drosophila specifically eliminates CSC-like cells in the brain and ovary without having discernable effects on normal stem cells. Brain CSC-like cells can arise from dedifferentiation of transit-amplifying progenitors upon Notch hyperactivation. eIF4E is up-regulated in these dedifferentiating progenitors, where it forms a feedback regulatory loop with the growth regulator dMyc to promote cell growth, particularly nucleolar growth, and subsequent ectopic neural stem cell (NSC) formation. Cell growth regulation is also a critical component of the mechanism by which Notch signaling regulates the self-renewal of normal NSCs. Our findings highlight the importance of Notch-regulated cell growth in stem cell maintenance and reveal a stronger dependence on eIF4E function and cell growth by CSCs, which might be exploited therapeutically.
View details for DOI 10.1101/gad.171959.111
View details for Web of Science ID 000298404400009
View details for PubMedID 22190460
Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression
2010; 466 (7306): 637-U9
Gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial as well as sporadic Parkinson's disease characterized by age-dependent degeneration of dopaminergic neurons. The molecular mechanism of LRRK2 action is not known. Here we show that LRRK2 interacts with the microRNA (miRNA) pathway to regulate protein synthesis. Drosophila e2f1 and dp messenger RNAs are translationally repressed by let-7 and miR-184*, respectively. Pathogenic LRRK2 antagonizes these miRNAs, leading to the overproduction of E2F1/DP, previously implicated in cell cycle and survival control and shown here to be critical for LRRK2 pathogenesis. Genetic deletion of let-7, antagomir-mediated blockage of let-7 and miR-184* action, transgenic expression of dp target protector, or replacement of endogenous dp with a dp transgene non-responsive to let-7 each had toxic effects similar to those of pathogenic LRRK2. Conversely, increasing the level of let-7 or miR-184* attenuated pathogenic LRRK2 effects. LRRK2 associated with Drosophila Argonaute-1 (dAgo1) or human Argonaute-2 (hAgo2) of the RNA-induced silencing complex (RISC). In aged fly brain, dAgo1 protein level was negatively regulated by LRRK2. Further, pathogenic LRRK2 promoted the association of phospho-4E-BP1 with hAgo2. Our results implicate deregulated synthesis of E2F1/DP caused by the miRNA pathway impairment as a key event in LRRK2 pathogenesis and suggest novel miRNA-based therapeutic strategies.
View details for DOI 10.1038/nature09191
View details for Web of Science ID 000280412100056
View details for PubMedID 20671708
Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2008; 105 (19): 7070-7075
Mitochondria form dynamic tubular networks that undergo frequent morphological changes through fission and fusion, the imbalance of which can affect cell survival in general and impact synaptic transmission and plasticity in neurons in particular. Some core components of the mitochondrial fission/fusion machinery, including the dynamin-like GTPases Drp1, Mitofusin, Opa1, and the Drp1-interacting protein Fis1, have been identified. How the fission and fusion processes are regulated under normal conditions and the extent to which defects in mitochondrial fission/fusion are involved in various disease conditions are poorly understood. Mitochondrial malfunction tends to cause diseases with brain and skeletal muscle manifestations and has been implicated in neurodegenerative diseases such as Parkinson's disease (PD). Whether abnormal mitochondrial fission or fusion plays a role in PD pathogenesis has not been shown. Here, we show that Pink1, a mitochondria-targeted Ser/Thr kinase linked to familial PD, genetically interacts with the mitochondrial fission/fusion machinery and modulates mitochondrial dynamics. Genetic manipulations that promote mitochondrial fission suppress Drosophila Pink1 mutant phenotypes in indirect flight muscle and dopamine neurons, whereas decreased fission has opposite effects. In Drosophila and mammalian cells, overexpression of Pink1 promotes mitochondrial fission, whereas inhibition of Pink1 leads to excessive fusion. Our genetic interaction results suggest that Fis1 may act in-between Pink1 and Drp1 in controlling mitochondrial fission. These results reveal a cell biological role for Pink1 and establish mitochondrial fission/fusion as a paradigm for PD research. Compounds that modulate mitochondrial fission/fusion could have therapeutic value in PD intervention.
View details for DOI 10.1073/pnas.0711845105
View details for Web of Science ID 000255921200051
View details for PubMedID 18443288
Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon
2007; 449 (7158): 96-U70
Self-renewal and differentiation are cardinal features of stem cells. Asymmetric cell division provides one fundamental mechanism by which stem cell self-renewal and differentiation are balanced. A failure of this balance could lead to diseases such as cancer. During asymmetric division of stem cells, factors controlling their self-renewal and differentiation are unequally segregated between daughter cells. Numb is one such factor that is segregated to the differentiating daughter cell during the stem-cell-like neuroblast divisions in Drosophila melanogaster, where it inhibits self-renewal. The localization and function of Numb is cell-cycle-dependent. Here we show that Polo (ref. 13), a key cell cycle regulator, the mammalian counterparts of which have been implicated as oncogenes as well as tumour suppressors, acts as a tumour suppressor in the larval brain. Supernumerary neuroblasts are produced at the expense of neurons in polo mutants. Polo directly phosphorylates Partner of Numb (Pon, ref. 16), an adaptor protein for Numb, and this phosphorylation event is important for Pon to localize Numb. In polo mutants, the asymmetric localization of Pon, Numb and atypical protein kinase C are disrupted, whereas other polarity markers are largely unaffected. Overexpression of Numb suppresses neuroblast overproliferation caused by polo mutations, suggesting that Numb has a major role in mediating this effect of Polo. Our results reveal a biochemical link between the cell cycle and the asymmetric protein localization machinery, and indicate that Polo can inhibit progenitor self-renewal by regulating the localization and function of Numb.
View details for DOI 10.1038/nature06056
View details for Web of Science ID 000249233500043
View details for PubMedID 17805297
PAR-1 kinase phosphorylates Dlg and regulates its postsynaptic targeting at the Drosophila neuromuscular junction
2007; 53 (2): 201-215
Targeting of synaptic molecules to their proper location is essential for synaptic differentiation and plasticity. PSD-95/Dlg proteins have been established as key components of the postsynapse. However, the molecular mechanisms regulating the synaptic targeting, assembly, and disassembly of PSD-95/Dlg are not well understood. Here we show that PAR-1 kinase, a conserved cell polarity regulator, is critically involved in controlling the postsynaptic localization of Dlg. PAR-1 is prominently localized at the Drosophila neuromuscular junction (NMJ). Loss of PAR-1 function leads to increased synapse formation and synaptic transmission, whereas overexpression of PAR-1 has the opposite effects. PAR-1 directly phosphorylates Dlg at a conserved site and negatively regulates its mobility and targeting to the postsynapse. The ability of a nonphosphorylatable Dlg to largely rescue PAR-1-induced synaptic defects supports the idea that Dlg is a major synaptic substrate of PAR-1. Control of Dlg synaptic targeting by PAR-1-mediated phosphorylation thus constitutes a critical event in synaptogenesis.
View details for DOI 10.1016/j.neuron.2006.12.016
View details for Web of Science ID 000245126600007
View details for PubMedID 17224403
View details for PubMedCentralID PMC1855201
Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused inactivation of Drosophila Pink1 is rescued by by Parkin
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2006; 103 (28): 10793-10798
Mutations in Pink1, a gene encoding a Ser/Thr kinase with a mitochondrial-targeting signal, are associated with Parkinson's disease (PD), the most common movement disorder characterized by selective loss of dopaminergic neurons. The mechanism by which loss of Pink1 leads to neurodegeneration is not understood. Here we show that inhibition of Drosophila Pink1 (dPink1) function results in energy depletion, shortened lifespan, and degeneration of select indirect flight muscles and dopaminergic neurons. The muscle pathology was preceded by mitochondrial enlargement and disintegration. These phenotypes could be rescued by the wild type but not the pathogenic C-terminal deleted form of human Pink1 (hPink1). The muscle and dopaminergic phenotypes associated with dPink1 inactivation show similarity to that seen in parkin mutant flies and could be suppressed by the overexpression of Parkin but not DJ-1. Consistent with the genetic rescue results, we find that, in dPink1 RNA interference (RNAi) animals, the level of Parkin protein is significantly reduced. Together, these results implicate Pink1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in Drosophila.
View details for DOI 10.1073/pnas.0602493103
View details for Web of Science ID 000239047400046
View details for PubMedID 16818890
View details for PubMedCentralID PMC1502310
Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2005; 102 (38): 13670-13675
Parkinson's disease (PD) is the most common movement disorder characterized by dopaminergic dysfunction and degeneration. The cause of most PD cases is unknown, although postmortem studies have implicated the involvement of oxidative stress. The identification of familial PD-associated genes offers the opportunity to study mechanisms of PD pathogenesis in model organisms. Here, we show that DJ-1A, a Drosophila homologue of the familial PD-associated gene DJ-1, plays an essential role in oxidative stress response and neuronal maintenance. Inhibition of DJ-1A function through RNA interference (RNAi) results in cellular accumulation of reactive oxygen species, organismal hypersensitivity to oxidative stress, and dysfunction and degeneration of dopaminergic and photoreceptor neurons. To identify other genes that may interact with DJ-1A in regulating cell survival, we performed genetic interaction studies and identified components of the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway as specific modulators of DJ-1A RNAi-induced neurodegeneration. PI3K signaling suppresses DJ-1A RNAi phenotypes at least in part by reducing cellular reactive oxygen species levels. Consistent with the genetic interaction results, we also found reduced phosphorylation of Akt in DJ-1A RNAi animals, indicating an impairment of PI3K/Akt signaling by DJ-1A down-regulation. Together with recent findings in mammalian systems, these results implicate impairments of PI3K/Akt signaling and oxidative stress response in DJ-1-associated disease pathogenesis. We also observed impairment of PI3K/Akt signaling in the fly parkin model of PD, hinting at a common molecular event in the pathogenesis of PD. Manipulation of PI3K/Akt signaling may therefore offer therapeutic benefits for the treatment of PD.
View details for DOI 10.1073/pnas.0504610102
View details for Web of Science ID 000232115100057
View details for PubMedID 16155123
PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila
2004; 116 (5): 671-682
Multisite hyperphosphorylation of tau has been implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). However, the phosphorylation events critical for tau toxicity and mechanisms regulating these events are largely unknown. Here we show that Drosophila PAR-1 kinase initiates tau toxicity by triggering a temporally ordered phosphorylation process. PAR-1 directly phosphorylates tau at S262 and S356. This phosphorylation event is a prerequisite for the action of downstream kinases, including glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase-5 (Cdk5), to phosphorylate several other sites and generate disease-associated phospho-epitopes. The initiator role of PAR-1 is further underscored by the fact that mutating PAR-1 phosphorylation sites causes a much greater reduction of overall tau phosphorylation and toxicity than mutating S202, one of the downstream sites whose phosphorylation depends on prior PAR-1 action. These findings begin to differentiate the effects of various phosphorylation events on tau toxicity and provide potential therapeutic targets.
View details for Web of Science ID 000221499700008
View details for PubMedID 15006350
Adherens junctions inhibit asymmetric division in the Drosophila epithelium
2001; 409 (6819): 522-525
Asymmetric division is a fundamental mechanism for generating cellular diversity. In the central nervous system of Drosophila, neural progenitor cells called neuroblasts undergo asymmetric division along the apical-basal cellular axis. Neuroblasts originate from neuroepithelial cells, which are polarized along the apical-basal axis and divide symmetrically along the planar axis. The asymmetry of neuroblasts might arise from neuroblast-specific expression of the proteins required for asymmetric division. Alternatively, both neuroblasts and neuroepithelial cells could be capable of dividing asymmetrically, but in neuroepithelial cells other polarity cues might prevent asymmetric division. Here we show that by disrupting adherens junctions we can convert the symmetric epithelial division into asymmetric division. We further confirm that the adenomatous polyposis coli (APC) tumour suppressor protein is recruited to adherens junctions, and demonstrate that both APC and microtubule-associated EB1 homologues are required for the symmetric epithelial division along the planar axis. Our results indicate that neuroepithelial cells have all the necessary components to execute asymmetric division, but that this pathway is normally overridden by the planar polarity cue provided by adherens junctions.
View details for Web of Science ID 000166570500050
View details for PubMedID 11206549
Partner of numb colocalizes with numb during mitosis and directs numb asymmetric localization in Drosophila neural and muscle progenitors
1998; 95 (2): 225-235
During mitosis of multiple types of precursor cells in Drosophila, Numb is asymmetrically distributed between the two daughter cells and confers distinct daughter cell fates. Here we report the identification of a novel gene product, Partner of Numb (PON), based on its physical interaction with Numb. PON is asymmetrically localized during mitosis and colocalizes with Numb. Loss of pon function disrupts Numb localization in muscle progenitors and delays Numb crescent formation in neural precursors. Moreover, ectopically expressed PON responds to the apical-basal polarity of epithelial cells and is sufficient to localize Numb basally. We propose that PON is one component of a multimolecular machinery that localizes Numb by responding to polarity cues conserved in neural precursors and epithelial cells.
View details for Web of Science ID 000076538300010
View details for PubMedID 9790529
The myriad roles of Miro in the nervous system: axonal transport of mitochondria and beyond
FRONTIERS IN CELLULAR NEUROSCIENCE
Mitochondrial rho GTPase (Miro) is a mitochondrial outer membrane protein containing two GTPase domains and two helix-loop-helix Ca(2+)-binding domains called EF hands. Pioneering genetic studies in Drosophila first revealed a key function of Miro in regulating the axonal transport of mitochondria, during which Miro forms a multi-protein transport complex with Milton and Kinesin heavy chain (KHC) to link trafficking mitochondria with the microtubule (MT) cytoskeleton. Recent studies showed that through binding to the EF hands of Miro and causing conformational changes of Miro and alteration of protein-protein interactions within the transport complex, Ca(2+) can alter the engagement of mitochondria with the MT/kinesin network, offering one mechanism to match mitochondrial distribution with neuronal activity. Despite the importance of the Miro/Milton/Kinesin complex in regulating mitochondrial transport in metazoans, not all components of the transport complex are conserved in lower organisms, and transport-independent functions of Miro are emerging. Here we review the diverse functions of the evolutionarily conserved Miro proteins that are relevant to the development, maintenance, and functioning of the nervous system and discuss the potential contribution of Miro dysfunction to the pathogenesis of diseases of the nervous system.
View details for DOI 10.3389/fncel.2014.00330
View details for Web of Science ID 000344534800001
View details for PubMedCentralID PMC4211407
- RNA metabolism in the pathogenesis of Parkinson's disease BRAIN RESEARCH 2014; 1584: 105-115
- Synergistic contribution of SMAD signaling blockade and high localized cell density in the differentiation of neuroectoderm from H9 cells BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2014; 452 (4): 895-900
Zinc binding directly regulates tau toxicity independent of tau hyperphosphorylation.
2014; 8 (3): 831-842
Tau hyperphosphorylation is thought to underlie tauopathy. Working in a Drosophila tauopathy model expressing a human Tau mutant (hTauR406W, or Tau(∗)), we show that zinc contributes to the development of Tau toxicity through two independent actions: by increasing Tau phosphorylation and, more significantly, by directly binding to Tau. Elimination of zinc binding through amino acid substitution of Cys residues has a minimal effect on phosphorylation levels yet essentially eliminates Tau toxicity. The toxicity of the zinc-binding-deficient mutant Tau(∗) (Tau(∗)C2A) and overexpression of native Drosophila Tau, also lacking the corresponding zinc-binding Cys residues, are largely impervious to zinc concentration. Importantly, restoration of zinc-binding ability to Tau(∗) by introduction of a zinc-binding residue (His) into the original Cys positions restores zinc-responsive toxicities in proportion to zinc-binding affinities. These results indicate zinc binding is a substantial contributor to tauopathy and have implications for therapy development.
View details for DOI 10.1016/j.celrep.2014.06.047
View details for PubMedID 25066125
Targeting PINK1 and MQC in brain tumors.
2014; 5 (10): 2864-2865
View details for PubMedID 24840210
Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila
JOURNAL OF CELL SCIENCE
2013; 126 (3): 838-849
Axon degeneration is observed at the early stages of many neurodegenerative conditions and this often leads to subsequent neuronal loss. We previously showed that inactivating the c-Jun N-terminal kinase (JNK) pathway leads to axon degeneration in Drosophila mushroom body (MB) neurons. To understand this process, we screened candidate suppressor genes and found that the Wallerian degeneration slow (Wld(S)) protein blocked JNK axonal degeneration. Although the nicotinamide mononucleotide adenylyltransferase (Nmnat1) portion of Wld(S) is required, we found that its nicotinamide adenine dinucleotide (NAD(+)) enzyme activity and the Wld(S) N-terminus (N70) are dispensable, unlike axotomy models of neurodegeneration. We suggest that Wld(S)-Nmnat protects against axonal degeneration through chaperone activity. Furthermore, ectopically expressed heat shock proteins (Hsp26 and Hsp70) also protected against JNK and Nmnat degeneration phenotypes. These results suggest that molecular chaperones are key in JNK- and Nmnat-regulated axonal protective functions.
View details for DOI 10.1242/jcs.117259
View details for Web of Science ID 000317281700013
View details for PubMedID 23264732
Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated A beta toxicity in Drosophila
The conserved kinases PAR-1/MARK are critically involved in processes such as asymmetric cell division, cell polarity and neuronal differentiation. Their deregulation has been implicated in diseases including Alzheimer's disease and cancer. Given the importance of PAR-1/MARK in health and disease, their activities need to be tightly controlled. However, little is known about the molecular mechanisms underlying their regulation in vivo. Here we show that in Drosophila, a phosphorylation-dependent ubiquitination mechanism restrains PAR-1 activation. Active PAR-1 generated by LKB1-controlled phosphorylation is targeted for ubiquitination and degradation by SCF (Skp, Cullin, F-box containing complex) (Slimb), whose action is antagonized by the deubiquitinating enzyme fat facets. This newly identified PAR-1-modifying module critically regulates synaptic morphology and tau-mediated postsynaptic toxicity of amyloid precursor protein (APP)/Aβ-42, the causative agents of Alzheimer's disease, at the Drosophila neuromuscular junction. Our results provide new insights into the regulation of PAR-1 in various physiological processes and offer new therapeutic strategies for diseases involving PAR-1/MARK deregulation.
View details for DOI 10.1038/ncomms2278
View details for Web of Science ID 000316356700079
View details for PubMedID 23271647
Closing the gap between clinic and cage: Sensori-motor and cognitive behavioural testing regimens in neurotoxin-induced animal models of Parkinson's disease
NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
2012; 36 (10): 2305-2324
Animal models that make use of chemical toxins to adversely affect the nigrostriatal dopaminergic pathway of rodents and primates have contributed significantly towards the development of symptomatic therapies for Parkinson's disease (PD) patients. Although their use in developing neuro-therapeutic and -regenerative compounds remains to be ascertained, toxin-based mammalian and a range of non-mammalian models of PD are important tools in the identification and validation of candidate biomarkers for earlier diagnosis, as well as in the development of novel treatments that are currently working their way into the clinic. Toxin models of PD have and continue to be important models to use for understanding the consequences of nigrostriatal dopamine cell loss. Functional assessment of these models is also a critical component for eventual translational success. Sensitive behavioural testing regimens for assessing the extent of dysfunction exhibited in the toxin models, the degree of protection or improvement afforded by potential treatment modalities, and the correlation of these findings with what is observed clinically in PD patients, ultimately determines whether a potential treatment moves to clinical trials. Here, we review existing published work that describes the use of such behavioural outcome measures associated with toxin models of parkinsonism. In particular, we focus on tests assessing sensorimotor and cognitive function, both of which are significantly and progressively impaired in PD.
View details for DOI 10.1016/j.neubiorev.2012.07.009
View details for Web of Science ID 000313613500011
View details for PubMedID 22910679
The synaptic function of LRRK2
BIOCHEMICAL SOCIETY TRANSACTIONS
2012; 40: 1047-1051
Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most frequent genetic lesions so far found in familial as well as sporadic forms of PD (Parkinson's disease), a neurodegenerative disease characterized by the dysfunction and degeneration of dopaminergic and other neuronal types. The molecular and cellular mechanisms underlying LRRK2 action remain poorly defined. Synaptic dysfunction has been increasingly recognized as an early event in the pathogenesis of major neurological disorders. Using Drosophila as a model system, we have shown that LRRK2 controls synaptic morphogenesis. Loss of dLRRK (Drosophila LRRK2) results in synaptic overgrowth at the Drosophila neuromuscular junction synapse, whereas overexpression of wild-type dLRRK, hLRRK2 (human LRRK2) or the pathogenic hLRRK2-G2019S mutant has the opposite effect. Alteration of LRRK2 activity also affects synaptic transmission in a complex manner. LRRK2 exerts its effects on synaptic morphology by interacting with distinct downstream effectors at the pre- and post-synaptic compartments. At the postsynapse, LRRK2 functionally interacts with 4E-BP (eukaryotic initiation factor 4E-binding protein) and the microRNA machinery, both of which negatively regulate protein synthesis. At the presynapse, LRRK2 phosphorylates and negatively regulates the microtubule-binding protein Futsch and functionally interacts with the mitochondrial transport machinery. These results implicate compartment-specific synaptic dysfunction caused by altered protein synthesis, cytoskeletal dynamics and mitochondrial transport in LRRK2 pathogenesis and offer a new paradigm for understanding and ultimately treating LRRK2-related PD.
View details for DOI 10.1042/BST20120113
View details for Web of Science ID 000309513200021
View details for PubMedID 22988863
Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease-Related Tau Phosphorylation Via PAR-1
2012; 8 (8)
Abnormal phosphorylation and toxicity of a microtubule-associated protein tau are involved in the pathogenesis of Alzheimer's disease (AD); however, what pathological conditions trigger tau abnormality in AD is not fully understood. A reduction in the number of mitochondria in the axon has been implicated in AD. In this study, we investigated whether and how loss of axonal mitochondria promotes tau phosphorylation and toxicity in vivo. Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1. These results suggest that an increase in tau phosphorylation at Ser262 through PAR-1 contributes to tau-mediated neurodegeneration under a pathological condition in which axonal mitochondria is depleted. Intriguingly, we found that knockdown of milton or Miro alone caused late-onset neurodegeneration in the fly brain, and this neurodegeneration could be suppressed by knockdown of Drosophila tau or PAR-1. Our results suggest that loss of axonal mitochondria may play an important role in tau phosphorylation and toxicity in the pathogenesis of AD.
View details for DOI 10.1371/journal.pgen.1002918
View details for Web of Science ID 000308529300069
View details for PubMedID 22952452
View details for PubMedCentralID PMC3431335
Kinase Signaling Dysfunction in Parkinson's Disease: A Reverse Genetic Approach in Drosophila
JOURNAL OF NEUROGENETICS
2012; 26 (2): 158-167
Drosophila genetics is one of the most powerful tools in modern biology. For many years, the "forward genetic" approach using Drosophila has been extraordinarily successful in elucidating the molecular pathways of many physiological processes and behaviors. Recently, the "reverse genetic" approach in Drosophila is increasingly being developed as a major tool for research in biology, especially in the study of human diseases. Parkinson's disease (PD) is the second most common neurodegenerative disease. Kinase signaling has been directly implicated in PD pathogenesis. Mutations in PTEN-induced kinase 1 (PINK1) cause PARK6 type PD, in which mitochondrial deficits are at the center of pathogenesis. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent genetic cause of both familial (PARK8 type with autosomal dominant inheritance) and sporadic PD. To understand the mechanism of PINK1- and LRRK2- mediated pathogenesis, reverse-engineered Drosophila models have been critical tools. Here the authors will discuss the usage of Drosophila models in their and other laboratories, and share scientific insights that originate from these studies, and discuss their experimental results of the effect of PINK1 on proteasome function. The authors will also comment on the different approaches taken in these lines of investigation.
View details for DOI 10.3109/01677063.2012.672499
View details for Web of Science ID 000306481300008
View details for PubMedID 22486164
Interaction of Notch Signaling Modulator Numb with alpha-Adaptin Regulates Endocytosis of Notch Pathway Components and Cell Fate Determination of Neural Stem Cells
JOURNAL OF BIOLOGICAL CHEMISTRY
2012; 287 (21): 17716-17728
The ability to balance self-renewal and differentiation is a hallmark of stem cells. In Drosophila neural stem cells (NSCs), Numb/Notch (N) signaling plays a key role in this process. However, the molecular and cellular mechanisms underlying Numb function in a stem cell setting remain poorly defined. Here we show that α-Adaptin (α-Ada), a subunit of the endocytic AP-2 complex, interacts with Numb through a new mode of interaction to regulate NSC homeostasis. In α-ada mutants, N pathway component Sanpodo and the N receptor itself exhibited altered trafficking, and N signaling was up-regulated in the intermediate progenitors of type II NSC lineages, leading to their transformation into ectopic NSCs. Surprisingly, although the Ear domain of α-Ada interacts with the C terminus of Numb and is important for α-Ada function in the sensory organ precursor lineage, it was dispensable in the NSCs. Instead, α-Ada could regulate Sanpodo, N trafficking, and NSC homeostasis by interacting with Numb through new domains in both proteins previously not known to mediate their interaction. This interaction could be bypassed when α-Ada was directly fused to the phospho-tyrosine binding domain of Numb. Our results identify a critical role for the AP-2-mediated endocytosis in regulating NSC behavior and reveal a new mechanism by which Numb regulates NSC behavior through N. These findings are likely to have important implications for cancer biology.
View details for DOI 10.1074/jbc.M112.360719
View details for Web of Science ID 000306373000070
View details for PubMedID 22474327
A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of A on synapses and dendritic spines
HUMAN MOLECULAR GENETICS
2012; 21 (6): 1384-1390
Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia in the elderly. Accumulating evidence supports soluble amyloid-β (Aβ) oligomers as the leading candidate for the causative agent in AD and synapses as the primary site of Aβ oligomer action. However, the molecular and cellular mechanisms by which Aβ oligomers cause synaptic dysfunction and cognitive impairments remain poorly understood. Using primary cultures of rat hippocampal neurons as a model system, we show that the partitioning defective-1 (PAR-1)/microtubule affinity-regulating kinase (MARK) family kinases act as critical mediators of Aβ toxicity on synapses and dendritic spines. Overexpression of MARK4 led to tau hyperphosphorylation, reduced expression of synaptic markers, and loss of dendritic spines and synapses, phenotypes also observed after Aβ treatment. Importantly, expression of a non-phosphorylatable form of tau with the PAR-1/MARK site mutated blocked the synaptic toxicity induced by MARK4 overexpression or Aβ treatment. To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels. Our results reveal a critical role for PAR-1/MARK kinases in AD pathogenesis and suggest PAR-1/MARK inhibitors as potential therapeutics for AD and possibly other tauopathies where aberrant tau hyperphosphorylation is involved.
View details for DOI 10.1093/hmg/ddr576
View details for Web of Science ID 000300721300015
View details for PubMedID 22156579
Synapses and Dendritic Spines as Pathogenic Targets in Alzheimer's Disease
Synapses are sites of cell-cell contacts that transmit electrical or chemical signals in the brain. Dendritic spines are protrusions on dendritic shaft where excitatory synapses are located. Synapses and dendritic spines are dynamic structures whose plasticity is thought to underlie learning and memory. No wonder neurobiologists are intensively studying mechanisms governing the structural and functional plasticity of synapses and dendritic spines in an effort to understand and eventually treat neurological disorders manifesting learning and memory deficits. One of the best-studied brain disorders that prominently feature synaptic and dendritic spine pathology is Alzheimer's disease (AD). Recent studies have revealed molecular mechanisms underlying the synapse and spine pathology in AD, including a role for mislocalized tau in the postsynaptic compartment. Synaptic and dendritic spine pathology is also observed in other neurodegenerative disease. It is possible that some common pathogenic mechanisms may underlie the synaptic and dendritic spine pathology in neurodegenerative diseases.
View details for DOI 10.1155/2012/247150
View details for Web of Science ID 000301151600001
View details for PubMedID 22474602
Mitochondrial dynamics and mitophagy in Parkinson's disease: disordered cellular power plant becomes a big deal in a major movement disorder
CURRENT OPINION IN NEUROBIOLOGY
2011; 21 (6): 935-941
Parkinson's disease (PD), the most common movement disorder, is characterized by age-dependent degeneration of dopaminergic neurons in the substantia nigra of the mid-brain. Non-motor symptoms of PD, however, precede the motor features caused by dysfunction of the dopaminergic system, suggesting that PD is a systemic disorder. Mitochondrial dysfunction has long been observed in PD patients and animal models, but the mechanistic link between mitochondrial dysfunction and PD pathogenesis is not well understood. Recent studies have revealed that genes associated with autosomal recessive forms of PD such as PINK1 and Parkin are directly involved in regulating mitochondrial morphology and maintenance, abnormality of which is also observed in the more common, sporadic forms of PD, although the autosomal recessive PDs lack Lewy-body pathology that is characteristic of sporadic PD. These latest findings suggest that at least some forms of PD can be characterized as a mitochondrial disorder. Whether mitochondrial dysfunction represents a unifying pathogenic mechanism of all PD cases remains a major unresolved question.
View details for DOI 10.1016/j.conb.2011.10.016
View details for Web of Science ID 000299972600015
View details for PubMedID 22048001
dp53 Restrains Ectopic Neural Stem Cell Formation in the Drosophila Brain in a Non-Apoptotic Mechanism Involving Archipelago and Cyclin E
2011; 6 (11)
Accumulating evidence suggests that tumor-initiating stem cells or cancer stem cells (CSCs) possibly originating from normal stem cells may be the root cause of certain malignancies. How stem cell homeostasis is impaired in tumor tissues is not well understood, although certain tumor suppressors have been implicated. In this study, we use the Drosophila neural stem cells (NSCs) called neuroblasts as a model to study this process. Loss-of-function of Numb, a key cell fate determinant with well-conserved mammalian counterparts, leads to the formation of ectopic neuroblasts and a tumor phenotype in the larval brain. Overexpression of the Drosophila tumor suppressor p53 (dp53) was able to suppress ectopic neuroblast formation caused by numb loss-of-function. This occurred in a non-apoptotic manner and was independent of Dacapo, the fly counterpart of the well-characterized mammalian p53 target p21 involved in cellular senescence. The observation that dp53 affected Edu incorporation into neuroblasts led us to test the hypothesis that dp53 acts through regulation of factors involved in cell cycle progression. Our results show that the inhibitory effect of dp53 on ectopic neuroblast formation was mediated largely through its regulation of Cyclin E (Cyc E). Overexpression of Cyc E was able to abrogate dp53's ability to rescue numb loss-of-function phenotypes. Increasing Cyc E levels by attenuating Archipelago (Ago), a recently identified transcriptional target of dp53 and a negative regulator of Cyc E, had similar effects. Conversely, reducing Cyc E activity by overexpressing Ago blocked ectopic neuroblast formation in numb mutant. Our results reveal an intimate connection between cell cycle progression and NSC self-renewal vs. differentiation control, and indicate that p53-mediated regulation of ectopic NSC self-renewal through the Ago/Cyc E axis becomes particularly important when NSC homeostasis is perturbed as in numb loss-of-function condition. This has important clinical implications.
View details for DOI 10.1371/journal.pone.0028098
View details for Web of Science ID 000298163400032
View details for PubMedID 22140513
The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons
HUMAN MOLECULAR GENETICS
2011; 20 (16): 3227-3240
PTEN-induced putative kinase 1 (PINK1) and Parkin act in a common pathway to regulate mitochondrial dynamics, the involvement of which in the pathogenesis of Parkinson's disease (PD) is increasingly being appreciated. However, how the PINK1/Parkin pathway influences mitochondrial function is not well understood, and the exact role of this pathway in controlling mitochondrial dynamics remains controversial. Here we used mammalian primary neurons to examine the function of the PINK1/Parkin pathway in regulating mitochondrial dynamics and function. In rat hippocampal neurons, PINK1 or Parkin overexpression resulted in increased mitochondrial number, smaller mitochondrial size and reduced mitochondrial occupancy of neuronal processes, suggesting that the balance of mitochondrial fission/fusion dynamics is tipped toward more fission. Conversely, inactivation of PINK1 resulted in elongated mitochondria, indicating that the balance of mitochondrial fission/fusion dynamics is tipped toward more fusion. Furthermore, overexpression of the fission protein Drp1 (dynamin-related protein 1) or knocking down of the fusion protein OPA1 (optical atrophy 1) suppressed PINK1 RNAi-induced mitochondrial morphological defect, and overexpression of PINK1 or Parkin suppressed the elongated mitochondria phenotype caused by Drp1 RNAi. Functionally, PINK1 knockdown and overexpression had opposite effects on dendritic spine formation and neuronal vulnerability to excitotoxicity. Finally, we found that PINK1/Parkin similarly influenced mitochondrial dynamics in rat midbrain dopaminergic neurons. These results, together with previous findings in Drosophila dopaminergic neurons, indicate that the PINK1/Parkin pathway plays conserved roles in regulating neuronal mitochondrial dynamics and function.
View details for DOI 10.1093/hmg/ddr235
View details for Web of Science ID 000293027100011
View details for PubMedID 21613270
View details for PubMedCentralID PMC3140825
Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fission
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2011; 108 (31): 12920-12924
Mutations in PTEN-induced kinase 1 (PINK1), a mitochondrial Ser/Thr kinase, cause an autosomal recessive form of Parkinson's disease (PD), PARK6. To investigate the mechanism of PINK1 pathogenesis, we used the Drosophila Pink1 knockout (KO) model. In mitochondria isolated from Pink1-KO flies, mitochondrial respiration driven by the electron transport chain (ETC) is significantly reduced. This reduction is the result of a decrease in ETC complex I and IV enzymatic activity. As a consequence, Pink1-KO flies also display a reduced mitochondrial ATP synthesis. Because mitochondrial dynamics is important for mitochondrial function and Pink1-KO flies have defects in mitochondrial fission, we explored whether fission machinery deficits underlie the bioenergetic defect in Pink1-KO flies. We found that the bioenergetic defects in the Pink1-KO can be ameliorated by expression of Drp1, a key molecule in mitochondrial fission. Further investigation of the ETC complex integrity in wild type, Pink1-KO, PInk1-KO/Drp1 transgenic, or Drp1 transgenic flies indicates that the reduced ETC complex activity is likely derived from a defect in the ETC complex assembly, which can be partially rescued by increasing mitochondrial fission. Taken together, these results suggest a unique pathogenic mechanism of PINK1 PD: The loss of PINK1 impairs mitochondrial fission, which causes defective assembly of the ETC complexes, leading to abnormal bioenergetics.
View details for DOI 10.1073/pnas.1107332108
View details for Web of Science ID 000293385700075
View details for PubMedID 21768365
Dronc caspase exerts a non-apoptotic function to restrain phospho-Numb-induced ectopic neuroblast formation in Drosophila
2011; 138 (11): 2185-2196
Drosophila neuroblasts have served as a model to understand how the balance of stem cell self-renewal versus differentiation is achieved. Drosophila Numb protein regulates this process through its preferential segregation into the differentiating daughter cell. How Numb restricts the proliferation and self-renewal potentials of the recipient cell remains enigmatic. Here, we show that phosphorylation at conserved sites regulates the tumor suppressor activity of Numb. Enforced expression of a phospho-mimetic form of Numb (Numb-TS4D) or genetic manipulation that boosts phospho-Numb levels, attenuates endogenous Numb activity and causes ectopic neuroblast formation (ENF). This effect on neuroblast homeostasis occurs only in the type II neuroblast lineage. We identify Dronc caspase as a novel binding partner of Numb, and demonstrate that overexpression of Dronc suppresses the effects of Numb-TS4D in a non-apoptotic and possibly non-catalytic manner. Reduction of Dronc activity facilitates ENF induced by phospho-Numb. Our findings uncover a molecular mechanism that regulates Numb activity and suggest a novel role for Dronc caspase in regulating neural stem cell homeostasis.
View details for DOI 10.1242/dev.058347
View details for Web of Science ID 000290430100004
View details for PubMedID 21558368
Drosophila tao Controls Mushroom Body Development and Ethanol-Stimulated Behavior through par-1
JOURNAL OF NEUROSCIENCE
2011; 31 (3): 1139-1148
In both mammalian and insect models of ethanol-induced behavior, low doses of ethanol stimulate locomotion. However, the mechanisms of the stimulant effects of ethanol on the CNS are mostly unknown. We have identified tao, encoding a serine-threonine kinase of the Ste20 family, as a gene necessary for ethanol-induced locomotor hyperactivity in Drosophila. Mutations in tao also affect behavioral responses to cocaine and nicotine, making flies resistant to the effects of both drugs. We show that tao function is required during the development of the adult nervous system and that tao mutations cause defects in the development of central brain structures, including the mushroom body. Silencing of a subset of mushroom body neurons is sufficient to reduce ethanol-induced hyperactivity, revealing the mushroom body as an important locus mediating the stimulant effects of ethanol. We also show that mutations in par-1 suppress both the mushroom body morphology and behavioral phenotypes of tao mutations and that the phosphorylation state of the microtubule-binding protein Tau can be altered by RNA interference knockdown of tao, suggesting that tao and par-1 act in a pathway to control microtubule dynamics during neural development.
View details for DOI 10.1523/JNEUROSCI.4416-10.2011
View details for Web of Science ID 000286373700038
View details for PubMedID 21248138
View details for PubMedCentralID PMC3045818
LRRK2 Kinase Regulates Synaptic Morphology through Distinct Substrates at the Presynaptic and Postsynaptic Compartments of the Drosophila Neuromuscular Junction
JOURNAL OF NEUROSCIENCE
2010; 30 (50): 16959-16969
Mutations in leucine-rich repeat kinase 2 (LRRK2) are linked to familial as well as sporadic forms of Parkinson's disease (PD), a neurodegenerative disease characterized by dysfunction and degeneration of dopaminergic and other types of neurons. The molecular and cellular mechanisms underlying LRRK2 action remain poorly defined. Here, we show that LRRK2 controls synaptic morphogenesis at the Drosophila neuromuscular junction. Loss of Drosophila LRRK2 results in synaptic overgrowth, whereas overexpression of Drosophila LRRK or human LRRK2 has opposite effects. Alteration of LRRK2 activity also affects neurotransmission. LRRK2 exerts its effects on synaptic morphology by interacting with distinct downstream effectors at the presynaptic and postsynaptic compartments. At the postsynapse, LRRK2 interacts with the previously characterized substrate 4E-BP, an inhibitor of protein synthesis. At the presynapse, LRRK2 phosphorylates and negatively regulates the microtubule (MT)-binding protein Futsch. These results implicate synaptic dysfunction caused by deregulated protein synthesis and aberrant MT dynamics in LRRK2 pathogenesis and offer a new paradigm for understanding and ultimately treating PD.
View details for DOI 10.1523/JNEUROSCI.1807-10.2010
View details for Web of Science ID 000285342300021
View details for PubMedID 21159966
View details for PubMedCentralID PMC3045823
Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in Drosophila melanogaster
2010; 6 (12)
Mutations in PINK1 and Parkin cause familial, early onset Parkinson's disease. In Drosophila melanogaster, PINK1 and Parkin mutants show similar phenotypes, such as swollen and dysfunctional mitochondria, muscle degeneration, energy depletion, and dopaminergic (DA) neuron loss. We previously showed that PINK1 and Parkin genetically interact with the mitochondrial fusion/fission pathway, and PINK1 and Parkin were recently proposed to form a mitochondrial quality control system that involves mitophagy. However, the in vivo relationships among PINK1/Parkin function, mitochondrial fission/fusion, and autophagy remain unclear; and other cellular events critical for PINK1 pathogenesis remain to be identified. Here we show that PINK1 genetically interacted with the protein translation pathway. Enhanced translation through S6K activation significantly exacerbated PINK1 mutant phenotypes, whereas reduction of translation showed suppression. Induction of autophagy by Atg1 overexpression also rescued PINK1 mutant phenotypes, even in the presence of activated S6K. Downregulation of translation and activation of autophagy were already manifested in PINK1 mutant, suggesting that they represent compensatory cellular responses to mitochondrial dysfunction caused by PINK1 inactivation, presumably serving to conserve energy. Interestingly, the enhanced PINK1 mutant phenotype in the presence of activated S6K could be fully rescued by Parkin, apparently in an autophagy-independent manner. Our results reveal complex cellular responses to PINK1 inactivation and suggest novel therapeutic strategies through manipulation of the compensatory responses.
View details for DOI 10.1371/journal.pgen.1001237
View details for Web of Science ID 000285578900015
View details for PubMedID 21151574
The Loss of PGAM5 Suppresses the Mitochondrial Degeneration Caused by Inactivation of PINK1 in Drosophila
2010; 6 (12)
PTEN-induced kinase 1 (PINK1), which is required for mitochondrial homeostasis, is a gene product responsible for early-onset Parkinson's disease (PD). Another early onset PD gene product, Parkin, has been suggested to function downstream of the PINK1 signalling pathway based on genetic studies in Drosophila. PINK1 is a serine/threonine kinase with a predicted mitochondrial target sequence and a probable transmembrane domain at the N-terminus, while Parkin is a RING-finger protein with ubiquitin-ligase (E3) activity. However, how PINK1 and Parkin regulate mitochondrial activity is largely unknown. To explore the molecular mechanism underlying the interaction between PINK1 and Parkin, we biochemically purified PINK1-binding proteins from human cultured cells and screened the genes encoding these binding proteins using Drosophila PINK1 (dPINK1) models to isolate a molecule(s) involved in the PINK1 pathology. Here we report that a PINK1-binding mitochondrial protein, PGAM5, modulates the PINK1 pathway. Loss of Drosophila PGAM5 (dPGAM5) can suppress the muscle degeneration, motor defects, and shorter lifespan that result from dPINK1 inactivation and that can be attributed to mitochondrial degeneration. However, dPGAM5 inactivation fails to modulate the phenotypes of parkin mutant flies. Conversely, ectopic expression of dPGAM5 exacerbated the dPINK1 and Drosophila parkin (dParkin) phenotypes. These results suggest that PGAM5 negatively regulates the PINK1 pathway related to maintenance of the mitochondria and, furthermore, that PGAM5 acts between PINK1 and Parkin, or functions independently of Parkin downstream of PINK1.
View details for DOI 10.1371/journal.pgen.1001229
View details for Web of Science ID 000285578900007
View details for PubMedID 21151955
Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila
HUMAN MOLECULAR GENETICS
2010; 19 (19): 3747-3758
Missense mutations in leucine-rich repeat kinase 2 (LRRK2)/Dardarin gene, the product of which encodes a kinase with multiple domains, are known to cause autosomal dominant late onset Parkinson's disease (PD). In the current study, we report that the gene product LRRK2 directly phosphorylates the forkhead box transcription factor FoxO1 and enhances its transcriptional activity. This pathway was found to be conserved in Drosophila, as the Drosophila LRRK2 homolog (dLRRK) enhanced the neuronal toxicity of FoxO. Importantly, FoxO mutants that were resistant to LRRK2/dLRRK-induced phosphorylation suppressed this neurotoxicity. Moreover, we have determined that FoxO targets hid and bim in Drosophila and human, respectively, are responsible for the LRRK2/dLRRK-mediated cell death. These data suggest that the cell death molecules regulated by FoxO are key factors during the neurodegeneration in LRRK2-linked PD.
View details for DOI 10.1093/hmg/ddq289
View details for Web of Science ID 000281718900005
View details for PubMedID 20624856
Atypical Cadherins Dachsous and Fat Control Dynamics of Noncentrosomal Microtubules in Planar Cell Polarity
2010; 19 (3): 389-401
How global organ asymmetry and individual cell polarity are connected to each other is a central question in studying planar cell polarity (PCP). In the Drosophila wing, which develops PCP along its proximal-distal (P-D) axis, we previously proposed that the core PCP mediator Frizzled redistributes distally in a microtubule (MT)-dependent manner. Here, we performed organ-wide analysis of MT dynamics by introducing quantitative in vivo imaging. We observed MTs aligning along the P-D axis at the onset of redistribution and a small but significant excess of + ends-distal MTs in the proximal region of the wing. This characteristic alignment and asymmetry of MT growth was controlled by atypical cadherins Dachsous (Ds) and Fat (Ft). Furthermore, the action of Ft was mediated in part by PAR-1. All these data support the idea that the active reorientation of MT growth adjusts cell polarity along the organ axis.
View details for DOI 10.1016/j.devcel.2010.08.004
View details for Web of Science ID 000282203100008
View details for PubMedID 20817616
Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease
HUMAN MOLECULAR GENETICS
2009; 18 (22): 4390-4404
Mutations in the LRRK2 gene are the most common genetic cause of familial Parkinson's disease (PD). However, its physiological and pathological functions are unknown. Therefore, we generated several independent Drosophila lines carrying WT or mutant human LRRK2 (mutations in kinase, COR or LRR domains, resp.). Ectopic expression of WT or mutant LRRK2 in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of LRRK2 increased lifespan and fertility of the flies. However, these flies were more sensitive to rotenone. LRRK2 expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by a concomitant expression of PINK1, DJ-1 or Parkin. This evidence suggests a genetic interaction between these PD-relevant genes.
View details for DOI 10.1093/hmg/ddp394
View details for Web of Science ID 000271107300015
View details for PubMedID 19692353
Mitochondrial Morphogenesis, Distribution, and Parkinson Disease: Insights From PINK1
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
2009; 68 (9): 953-963
The etiology of Parkinson disease (PD) has been assumed to be a complex combination of environmental factors, intrinsic cellular metabolic properties, and susceptible genetic alleles. The primary obstacles to the development of a neuroprotective therapy in PD include uncertainties with regard to the precise cause(s) of neuronal dysfunction and what to target. The discoveries of Mendelian genes associated with inherited forms of PD in the last 10 years have revolutionized the understanding of the cellular pathways leading to neuronal dysfunction. Common themes of the pathogenesis of PD are beginning to emerge with mitochondrial dysfunction at the center stage. In this review, we summarize our knowledge of the pathogenesis of PD, revisit some aspects of mitochondrial biology, and discuss the insights from the study of Pink1, a familial PD-associated gene. We propose that mitochondrial morphogenesis and distribution might be a novel and potential common paradigm for PD and other neurodegenerative disease research and that modulation of such mitochondrial processes may prove to be a valuable therapeutic avenue for PD.
View details for Web of Science ID 000269581300001
View details for PubMedID 19680148
Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson's disease
Parkinson's disease (PD) is the most common movement disorder. Extrapyramidal motor symptoms stem from the degeneration of the dopaminergic pathways in patient brain. Current treatments for PD are symptomatic, alleviating disease symptoms without reversing or retarding disease progression. Although the cause of PD remains unknown, several pathogenic factors have been identified, which cause dopaminergic neuron (DN) death in the substantia nigra (SN). These include oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity. Manipulation of these factors may allow the development of disease-modifying treatment strategies to slow neuronal death. Inhibition of DJ-1A, the Drosophila homologue of the familial PD gene DJ-1, leads to oxidative stress, mitochondrial dysfunction, and DN loss, making fly DJ-1A model an excellent in vivo system to test for compounds with therapeutic potential.In the present study, a Drosophila DJ-1A model of PD was used to test potential neuroprotective drugs. The drugs applied are the Chinese herb celastrol, the antibiotic minocycline, the bioenergetic amine coenzyme Q10 (coQ10), and the glutamate antagonist 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo[f]-quinoxaline (NBQX). All of these drugs target pathogenic processes implicated in PD, thus constitute mechanism-based treatment strategies. We show that celastrol and minocycline, both having antioxidant and anti-inflammatory properties, confer potent dopaminergic neuroprotection in Drosophila DJ-1A model, while coQ10 shows no protective effect. NBQX exerts differential effects on cell survival and brain dopamine content: it protects against DN loss but fails to restore brain dopamine level.The present study further validates Drosophila as a valuable model for preclinical testing of drugs with therapeutic potential for neurodegenerative diseases. The lower cost and amenability to high throughput testing make Drosophila PD models effective in vivo tools for screening novel therapeutic compounds. If our findings can be further validated in mammalian PD models, they would implicate drugs combining antioxidant and anti-inflammatory properties as strong therapeutic candidates for mechanism-based PD treatment.
View details for DOI 10.1186/1471-2202-10-109
View details for Web of Science ID 000270558900001
View details for PubMedID 19723328
Recent advances in using Drosophila to model neurodegenerative diseases
2009; 14 (8): 1008-1020
Neurodegenerative diseases are progressive disorders of the nervous system that affect the function and maintenance of specific neuronal populations. Most disease cases are sporadic with no known cause. The identification of genes associated with familial cases of these diseases has enabled the development of animal models to study disease mechanisms. The model organism Drosophila has been successfully used to study pathogenic mechanisms of a wide range of neurodegenerative diseases. Recent genetic studies in the Drosophila models have provided new insights into disease mechanisms, emphasizing the roles played by mitochondrial dynamics, RNA (including miRNA) function, protein translation, and synaptic plasticity and differentiation. It is anticipated that Drosophila models will further our understanding of mechanisms of neurodegeneration and facilitate the development of novel and rational treatments for these debilitating neurodegenerative diseases.
View details for DOI 10.1007/s10495-009-0347-5
View details for Web of Science ID 000268510200009
View details for PubMedID 19373559
Mitochondrial dynamics and neurodegeneration
CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS
2009; 9 (3): 212-219
Mitochondria are key organelles in eukaryotic cells that not only generate adenosine triphosphate but also perform such critical functions as hosting essential biosynthetic pathways, calcium buffering, and apoptotic signaling. In vivo, mitochondria form dynamic networks that undergo frequent morphologic changes through fission and fusion. In neurons, the imbalance of mitochondrial fission/fusion can influence neuronal physiology, such as synaptic transmission and plasticity, and affect neuronal survival. Core components of the mitochondrial fission/fusion machinery have been identified through genetic studies in model organisms. Mutations in some of these genes in humans have been linked to rare neuro-degenerative diseases such as Charcot-Marie-Tooth subtype 2A and autosomal dominant optic atrophy. Recent studies also have implicated aberrant mitochondrial fission/fusion in the pathogenesis of more common neurodegenerative diseases such as Parkinson's disease. These studies establish mitochondrial dynamics as a new paradigm for neurodegenerative disease research. Compounds that modulate mitochondrial fission/fusion could have therapeutic value in disease intervention.
View details for DOI 10.1007/s11910-009-0032-7
View details for Web of Science ID 000264885600005
View details for PubMedID 19348710
Drosophila Models of Neurodegenerative Diseases
ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE
2009; 4: 315-342
Neurodegenerative diseases are progressive disorders of the nervous system that affect specific cellular populations in the central and peripheral nervous systems. Although most cases are sporadic, genes associated with familial cases have been identified, thus enabling the development of animal models. Invertebrates such as Drosophila have recently emerged as model systems for studying mechanisms of neurodegeneration in several major neurodegenerative diseases. These models are also excellent in vivo systems for the testing of therapeutic compounds. Genetic studies using these animal models have provided novel insights into the disease process. We anticipate that further exploration of the animal models will further our understanding of mechanisms of neurodegeneration as well as facilitate the development of rational treatments for debilitating degenerative diseases.
View details for DOI 10.1146/annurev.pathol.3.121806.151529
View details for Web of Science ID 000268071700013
View details for PubMedID 18842101
Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila
2008; 27 (18): 2432-2443
Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent molecular lesions so far found in Parkinson's disease (PD), an age-dependent neurodegenerative disorder affecting dopaminergic (DA) neuron. The molecular mechanisms by which mutations in LRRK2 cause DA degeneration in PD are not understood. Here, we show that both human LRRK2 and the Drosophila orthologue of LRRK2 phosphorylate eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP), a negative regulator of eIF4E-mediated protein translation and a key mediator of various stress responses. Although modulation of the eIF4E/4E-BP pathway by LRRK2 stimulates eIF4E-mediated protein translation both in vivo and in vitro, it attenuates resistance to oxidative stress and survival of DA neuron in Drosophila. Our results suggest that chronic inactivation of 4E-BP by LRRK2 with pathogenic mutations deregulates protein translation, eventually resulting in age-dependent loss of DA neurons.
View details for DOI 10.1038/emboj.2008.163
View details for Web of Science ID 000259260100008
View details for PubMedID 18701920
Activation of PAR-1 kinase and stimulation of tau phosphorylation by diverse signals require the tumor suppressor protein LKB1
JOURNAL OF NEUROSCIENCE
2007; 27 (3): 574-581
Aberrant phosphorylation of tau is associated with a number of neurodegenerative diseases, including Alzheimer's disease (AD). The molecular mechanisms by which tau phosphorylation is regulated under normal and disease conditions are not well understood. Microtubule affinity regulating kinase (MARK) and PAR-1 have been identified as physiological tau kinases, and aberrant phosphorylation of MARK/PAR-1 target sites in tau has been observed in AD patients and animal models. Here we show that phosphorylation of PAR-1 by the tumor suppressor protein LKB1 is required for PAR-1 activation, which in turn promotes tau phosphorylation in Drosophila. Diverse stress stimuli, such as high osmolarity and overexpression of the human beta-amyloid precursor protein, can promote PAR-1 activation and tau phosphorylation in an LKB1-dependent manner. These results reveal a new function for the tumor suppressor protein LKB1 in a signaling cascade through which the phosphorylation and function of tau is regulated by diverse signals under physiological and pathological conditions.
View details for DOI 10.1523/JNEUROSCI.5094-06.2007
View details for Web of Science ID 000243540700013
View details for PubMedID 17234589
- Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1 The Journal of Neuroscience 2007; 27 (3): 574-581
- HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites FASEB JOURNAL 2006; 20 (2): 753-?
Understanding and treating neurodegeneration: insights from the flies
2005; 27 (3): 225-239
Drosophila has recently emerged as a model system for studying mechanisms of neurodegeneration. Genetic models for most of the major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), polyglutamine diseases, and tauopathies, have been successfully established. Pharmacological models of some of these diseases have also been created. Genetic modifier screens using these models have uncovered previously implicated mechanisms and molecules as well as novel ones. Fly models have turned out to be excellent system for the in vivo testing of therapeutic potentials of candidate compounds. It is anticipated that further exploration of the fly models will not only provide novel insights into mechanisms of neurodegeneration but also lead to the development of rational treatment of those debilitating degenerative diseases.
View details for DOI 10.1007/s11357-005-2917-y
View details for Web of Science ID 000243169500006
View details for PubMedID 23598655
- Putting a PARKINg brake on neurodegeneration MOLECULAR PSYCHIATRY 2004; 9 (1): 6-7
RNA interference technologies for understanding and treating neurodegenerative diseases
2004; 6 (1): 1-12
RNA interference (RNAi) is an evolutionarily conserved process that silences gene expression through double-stranded RNA species in a sequence-specific manner. With the completion of genome sequencing in multiple organisms, RNAi provides an efficient reverse genetics tool to reveal gene functions on a genome-wide scale. Conditional/inducible RNAi offers a new way to analyze gene function at different developmental stages and to create a new generation of animal models of human diseases. The sequence-specificity of RNAi and the fact that it is a naturally occurring process in human make it an excellent therapeutic tool for a wide range of diseases. This article provides a brief review of the current understandings of the mechanism of RNAi and its application to the nervous system, with particular focus on its application to understand mechanisms of neurodegenerative diseases. The prospects of the application of RNAi in clinical setting to treat these devastating diseases will also be presented.
View details for Web of Science ID 000231119800001
View details for PubMedID 15781973
Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila
2003; 37 (6): 911-924
Parkin, an E3 ubiquitin ligase that degrades proteins with aberrant conformations, is associated with autosomal recessive juvenile Parkinsonism (AR-JP). The molecular basis of selective neuronal death in AR-JP is unknown. Here we show in an organismal system that panneuronal expression of Parkin substrate Pael-R causes age-dependent selective degeneration of Drosophila dopaminergic (DA) neurons. Coexpression of Parkin degrades Pael-R and suppresses its toxicity, whereas interfering with endogenous Drosophila Parkin function promotes Pael-R accumulation and augments its toxicity. Furthermore, overexpression of Parkin can mitigate alpha-Synuclein-induced neuritic pathology and suppress its toxicity. Our study implicates Parkin as a central player in the molecular pathway of Parkinson's disease (PD) and suggests that manipulating Parkin expression may provide a novel avenue of PD therapy.
View details for Web of Science ID 000181899600006
View details for PubMedID 12670421
PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling
NATURE CELL BIOLOGY
2001; 3 (7): 628-636
Wnt signalling regulates beta-catenin-dependent developmental processes through the Dishevelled protein (Dsh). Dsh regulates two distinct pathways, one mediated by beta-catenin and the other by Jun kinase (JNK). We have purified a Dsh-associated kinase from Drosophila that encodes a homologue of Caenorhabditis elegans PAR-1, a known determinant of polarity during asymmetric cell divisions. Treating cells with Wnt increases endogenous PAR-1 activity coincident with Dsh phosphorylation. PAR-1 potentiates Wnt activation of the beta-catenin pathway but blocks the JNK pathway. Suppressing endogenous PAR-1 function inhibits Wnt signalling through beta-catenin in mammalian cells, and Xenopus and Drosophila embryos. PAR-1 seems to be a positive regulator of the beta-catenin pathway and an inhibitor of the JNK pathway. These findings show that PAR-1, a regulator of polarity, is also a modulator of Wnt-beta-catenin signalling, indicating a link between two important developmental pathways.
View details for Web of Science ID 000169727000013
View details for PubMedID 11433294
Drosophila par-1 is required for oocyte differentiation and microtubule organization
2001; 11 (2): 75-87
Drosophila oocyte determination involves a complex process by which a single cell within an interconnected cyst of 16 germline cells differentiates into an oocyte. This process requires the asymmetric accumulation of both specific messenger RNAs and proteins within the future oocyte as well as the proper organization of the microtubule cytoskeleton, which together with the fusome provides polarity within the developing germline cyst.In addition to its previously described late oogenic role in the establishment of anterior-posterior polarity and subsequent embryonic axis formation, the Drosophila par-1 gene is required very early in the germline for establishing cyst polarity and for oocyte specification. Germline clonal analyses, for which we used a protein null mutation, reveal that Drosophila par-1 (par-1) is required for the asymmetric accumulation of oocyte-specific factors as well as the proper organization of the microtubule cytoskeleton. Similarly, somatic clonal analyses indicate that par-1 is required for microtubule stabilization in follicle cells. The PAR-1 protein is localized to the fusome and ring canals within the developing germline cyst in direct contact with microtubules. Likewise, in the follicular epithelium, PAR-1 colocalizes with microtubules along the basolateral membrane. However, in either case PAR-1 localization is independent of microtubules.The Drosophila par-1 gene plays at least two essential roles during oogenesis; it is required early in the germline for organization of the microtubule cytoskeleton and subsequent oocyte determination, and it has a second, previously described role late in oogenesis in axis formation. In both cases, par-1 appears to exert its effects through the regulation of microtubule dynamics and/or stability, and this finding is consistent with the defined role of the mammalian PAR-1 homologs.
View details for Web of Science ID 000169076200016
View details for PubMedID 11231123
Control of cell divisions in the nervous system: Symmetry and asymmetry
ANNUAL REVIEW OF NEUROSCIENCE
2000; 23: 531-556
The diverse cell types in the nervous system are derived from neural progenitor cells. Neural progenitors can undergo symmetric divisions to expand cell population or asymmetric divisions to generate diverse cell types. Furthermore, neural progenitors must exit the cell cycle in a developmentally regulated manner to allow for terminal differentiation. The patterns of neural progenitor divisions have been characterized in vertebrates and invertebrates. During the course of nervous system development, extrinsic and intrinsic cues dictate the division patterns of neural progenitors by influencing their cell cycle behavior and cellular polarity. The identification in Drosophila of asymmetrically distributed fate determinants, adapter molecules, and polarity organizing molecules that participate in asymmetric neural progenitor divisions should provide points of entry for studying similar asymmetric divisions in vertebrates.
View details for Web of Science ID 000086730500018
View details for PubMedID 10845074
Modes of protein movement that lead to the asymmetric localization of partner of numb during Drosophila neuroblast division
1999; 4 (6): 883-891
Partner of Numb (Pon) colocalizes with the determinant Numb and is required for its proper asymmetric localization in Drosophila. How the asymmetric localization of Pon is accomplished is not well understood. Here, we show that Pon localization takes place at the protein level and that its C-terminal region is necessary and sufficient for asymmetric localization. Fusion of the Pon localization domain with green fluorescent protein (GFP) allowed monitoring of the localization process in living embryos. Upon a neuroblast's entry into mitosis, Pon is recruited from the cytoplasm to the cortex. Cortically recruited Pon can move apically or basally within the two-dimensional confines of the cortex. This movement can occur when myosin motor activity is inhibited. However, the restriction of Pon to the basal cortex requires both actomyosin and Inscuteable.
View details for Web of Science ID 000084485900001
View details for PubMedID 10635314
Flamingo controls the planar polarity of sensory bristles and asymmetric division of sensory organ precursors in Drosophila
1999; 9 (21): 1247-1250
The sensory bristles of the fruit fly Drosophila are organized in a polarized fashion such that bristles on the thorax point posteriorly. These bristles are derived from asymmetric division of sensory organ precursors (SOPs). The Numb protein, which is localized asymmetrically in a cortical crescent in each SOP, segregates into only one of the two daughter cells during cell division, thereby conferring distinct fates to the daughter cells  . In neuroblasts, establishment of apical-basal polarity by the protein Inscuteable is crucial for orienting asymmetric division, but this is not the case for division of SOPs . Instead, the Frizzled (Fz) protein mediates a planar polarity signal that controls the anteroposteriorly oriented first division (pl) of SOPs . Here, we report that Flamingo (Fmi), a seven-transmembrane cadherin , controls the planar polarity of sensory bristles and the orientation of the SOP pl division. Both the loss of function and overexpression of fmi disrupted bristle polarity. During mitosis of the SOP, the axis of the pl division and the positioning of the Numb crescent were randomized in the absence of Fmi activity. Overexpression of Fmi and Fz caused similar effects. The dependence of proper Fmi localization on Fz activity suggests that Fmi functions downstream of Fz in controlling planar polarity. We also present evidence suggesting that Fz also functions in the Wingless pathway to pattern sensory organs.
View details for Web of Science ID 000083492800018
View details for PubMedID 10556092
Asymmetric cell division: Lessons from flies and worms
CURRENT OPINION IN GENETICS & DEVELOPMENT
1998; 8 (4): 392-399
Insights into the mechanisms of asymmetric cell division have recently been obtained from studies in genetically amenable systems such as Drosophila and Caenorhabditis elegans. These studies have emphasized the importance of cortically localized polarity organizing molecules, adapter molecules, and the actin cytoskeleton in controlling unequal segregation of cell-fate determinants and spindle orientation. The control of asymmetric cell divisions by Wnt signaling in C. elegans and Frizzled signaling in Drosophila reveals additional mechanisms for modulating cellular polarity and suggests that there are some similarities between the two systems.
View details for Web of Science ID 000075603800003
View details for PubMedID 9729713